Our appreciation of the role of Fc receptors in immunobiology continues to expand with important roles in phagocytes, B cells and dendritic cell biology. In humans, members of the three families of highly homologous IgG receptors (FcRI, FcRII, FcRIa) have typically been conceptualized as "activating" or "inhibitory" receptors. Indeed, in seminal work in mouse models from several laboratories, it has been shown that the absence of gamma-chain-associated activating receptors (FcRIa, FcRIII/IV) mitigates both acute and sustained inflammatory disease while the absence of the inhibitory FcRllb receptor exacerbates inflammatory disease. However, the recognition of non-immunoglobulin ligands for FcR and of the multiple functions for FcR, underscore intricate, and perhaps more diverse, roles for these receptors in organismal homeostasis, in the afferent host immune response, and in efferent inflammatory cell programs. We, and others, have identified differences in the structure and properties of the extracellular domains of both FcgR and Fc-alphaR which influence function through different affinities, differential binding of Ig subclasses and naturally occurring genetic variants which modulate these properties. While these differences have been considered in the context of the dichotomous "activating and inhibitory" framework, several observations indicate that there is another dimension of important properties which we hypothesize is conferred by the unique cytoplasmic domain sequences of the "activating" receptors associated with the FceRI common gamma-chain. Indeed, our data indicate a novel and unanticipated role in function for the unique cytoplasmic domains, not only for IgG receptors but also for the gamma-chain-associated IgA receptor. The cytoplasmic domains of the alpha-chains serve not only as a scaffold for molecular assemblies but also act as a "molecular switch" determining both the type and intensity of receptor-initiated function. Accordingly, the specific aims of this proposal are: 1. using a series of alpha-chain receptor chimeras to control for EC and TM, to characterize the unique contributions of each alpha cytoplasmic domain from the human gamma-chain-associated receptors. 2. to define the unique alpha-chain cytoplasmic domain binding partners of gamma-chain-associated receptors and identify the key points of regulation. 3. to establish the contributions of adaptor binding proteins and compare-the differential function of the alpha cytoplasmic domains for human CD64 (FcRIa) and CD16 (FcRllla) in receptor chimeras in vivo. 4. to identify unique human alpha cytoplasmic domain allelic variants for the gamma-chain associated receptors, to determine their functional characteristics and to establish their association with altered host defense and autoimmune disease (eg, rheumatoid arthritis, celiac disease, systemic vasculitis).